PROJECT SUMMARY Postpartum depression (PPD) affects at least 15% of new mothers, making it one of the most common mental health conditions in women. PPD is not only detrimental for the mother's well-being, it is also known to have a damaging effect on mother-infant interactions which can negatively impact offspring development. Despite its prevalence and adverse consequences for women and their children, the mechanisms that contribute to the development of PPD remain unclear. Our long-term goal is to identify novel mediators that may be responsible for mood disturbance and impaired maternal care in PPD in order to better understand the pathophysiology of the disorder and ultimately develop new treatment strategies. To achieve that goal we propose to use an animal model that incorporates gestational stress, a major risk factor for PPD that we have shown: 1) recapitulates the critical behavioral symptoms found in depressed human mothers (i.e. behavioral despair, anhedonia, maternal care deficits) and 2) produces neural abnormalities (i.e. dendritic spine loss) in key mood regulating brain regions that have been implicated in PPD, including the medial prefrontal cortex and nucleus accumbens. Using this model, we will investigate the neuroimmune underpinnings of PPD by focusing on microglia, the primary innate immune cells of the brain that are known to be important regulators of mood and neuroplasticity. The central hypothesis of this exploratory proposal is that gestational stress perturbs the peripartum neuroimmune environment and this has an etiological role in postpartum depressive- like symptomology and the accompanying reduction in dendritic spines. We will employ behavioral, neuroanatomical, immunological, biochemical, and pharmacological approaches to test our central hypothesis in two Specific Aims. Aim 1 will delineate how gestational stress induces dysregulation of microglia in the peripartum brain. Aim 2 will determine the extent to which immunomodulatory interventions can prevent or mitigate the detrimental effects of gestational stress on postpartum mood, maternal care, and neuroplasticity. Overall, these studies will push research related to women's mental health during the postpartum period forward by potentially uncovering a previously unknown role of the neuroimmune system in maternal depression.